The calcium receptor, also called the calcium sensing receptor (also referred to as “CaSR”), was cloned from bovine thyroid in 1993 as G-protein coupled seven-transmembrane receptor (G-protein coupled receptor; GPCR) that senses extracellular calcium (Ca2+) (Non-patent Document 1). The calcium receptor has a function of altering the intracellular Ca2+ concentration by sensing extracellular Ca2+, thereby regulating production of hormones or the like involved in Ca2+ metabolic regulation, as typified by parathyroid hormone.
Recently, cinacalcet (CCT), a calcium receptor agonist, was found to have an action of suppressing secretion of parathyroid hormone by acting on the calcium receptor of parathyroid to enhance Ca2+ sensitivity of the calcium receptor (Non-patent Document 2), and it has been marketed as a therapeutic drug for secondary hyperparathyroidism of dialysis patients (Non-patent Document 3).
In addition, the calcium receptor was also found to be expressed in kidney, brain, thyroid, bones and digestive tracts, and thus considered to be involved in various diseases.
As compounds having a CaSR activating effect, other than glutathione, for example, gamma-glutamyl peptide derivatives (Non-patent Documents 4 and 9), pyrrolidine derivatives (Patent Document 1) and the like are known. In addition, CaSR agonists such as a gamma-glutamyl peptide derivative have been reported to be useful as a prophylactic or therapeutic agent for diarrhea (Patent Document 2), a prophylactic or therapeutic agent for acid secretion-related diseases such as gastric ulcer, duodenal ulcer and reflux esophagitis (Patent Document 3), a therapeutic agent for diabetes or obesity (Patent Document 4), and further as an immunostimulator (Patent Document 5). Furthermore, Patent Document 6 and Non-patent Document 9 describe that compounds having CaSR agonistic activity are also useful as agent for imparting kokumi.
These compounds, however, are structurally different from the alkylamine derivatives of the present invention.
Meanwhile, a gamma-glutamyl anilide derivative, among the alkylamine derivatives, is known to be used as a substrate for enzymatic activity (Non-patent Document 5 and Patent Document 7) as well as for its application as an antimicrobial agent or an anti-allergic agent (Non-patent Document 6 and Patent Document 8) and its application as an analytical reagent (Non-patent Documents 7 and 11). Moreover, an L-2-amino-3-N′-substituted ureidopropanoic acid derivative is known for its application as a synthetic intermediate of an asparagine analog employed as an anticancer agent (Non-patent Document 8). The alkylamine derivative is known as a leukotriene A4 inhibitor for application against inflammatory diseases (Non-patent Document 10). The alkylamine derivative is also known for its application as an anticancer agent (Non-patent Document 12).
The above-mentioned compounds, however, have not been known for their applications as pharmaceutical agents with a CaSR agonistic effect or applications as seasonings.